Methods and compositions for treating conditions associated with infection and/or inflammation

ABSTRACT

The present invention provides methods and compositions for treating and preventing conditions characterized by infection and/or inflammation, especially of the eyes, ears, nose, and/or throat. The methods of the invention involve administering hypohalous acid to the patient, such as in the form of a composition described herein.

This application is a National Stage of PCT/US08/51208, filed Jan. 16,2008, which claims the benefit of U.S. Provisional Application No.60/885,122, filed Jul. 16, 2007, each of which are hereby incorporatedby reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for treatingor preventing conditions characterized by infection and/or inflammationby administering hypohalous acid to the affected or susceptible areas.The invention is applicable to conditions affecting, for example, theeye, ear, nose, mouth, and/or throat.

BACKGROUND OF THE INVENTION

Many health conditions are characterized by infection and/orinflammation, such as various conditions of the eyes, ears, nose, andthroat. While often difficult to discern underlying causes in aparticular case, such conditions may be treated with, for example,topical or systemic antibiotics, antivirals, and/or anti-inflammatoryagents depending on the suspected etiology. Such treatments are howeverlimited by microbial resistance, drug toxicity, irritation, and/orhypersensitivity that may develop. Methods and compositions for broadly,effectively, and safely treating infected regions and/or inflammatoryconditions of the body are needed.

For example, conjunctivitis, commonly known as pink eye, is aninflammation of the conjunctiva, the outer-most layer of the eye thatcovers the sclera. While many of the signs and symptoms ofconjunctivitis are relatively non-specific, there are several etiologiesthat may be causative in a given case. The three most common causes ofconjunctivitis are bacterial infection, viral infection, or an allergicreaction.

Bacterial conjunctivitis is commonly caused by staphylococcus andstreptococcus bacteria, and in the case of newborns, may result fromvertical transmission of Neisseria or Chlamydia from an infected mother.The symptoms and the severity of bacterial conjunctivitis depend on thebacteria involved. For example, when caused by a pyogenic bacteria, theinfection may produce a stringy, opaque discharge that may cause mattingof the eyelids. There may be severe crusting of the infected eye andsurrounding skin. Where bacterial conjunctivitis is suspected, thecondition is treated with an antibiotic effective for a broad range ofbacteria. Where initial antibiotic treatment is unsuccessful, bacterialcultures can be initiated to guide treatment, although negative resultsare fairly common since some bacteria implicated in conjunctivitis arenot easily cultured by usual laboratory culturing methods. Bacterialconjunctivitis can be quite contagious, and easily spreads from one eyeto the other and from person to person. Ear infections commonly occur inchildren with persistent bacterial conjunctivitis.

Viral conjunctivitis may be associated with an upper respiratory tractinfection, cold, or sore throat and may be caused by adenovirus. Viralconjunctivitis sometimes produces a water discharge. While the infectionruns its course, the symptoms of viral conjunctivitis can be relievedwith cool compresses and artificial tears. For more severe cases,topical steroid drops may be prescribed to reduce the discomfort frominflammation. These are not without side effects, especially withprolonged use.

Allergic conjunctivitis occurs more frequently among those with allergicconditions and may be caused by intolerance to substances such ascosmetics, medications or fumes. For allergic conjunctivitis, coolcompresses and artificial tears sometimes relieve discomfort in mildcases. In more severe cases, non-steroidal anti-inflammatory medicationsand antihistamines may be prescribed. Some patients with persistentallergic eye infections may also require topical steroid drops.

Blepharitis is an inflammation of the eyelid margins, and is usuallycaused by an infection of Staphylococcus aureus. Treatment generallyinvolves cleaning the lid and applying a topical antistaphylococcalantibiotic. Blepharitis can lead to a chalazion, or lead to a stye(hordeolum).

A chalzion is a cyst in the eyelid caused by inflammation of a blockedmeibomian gland, usually on the upper eyelid. A chalazion may spawnbacterial infection. When the condition does not resolve on its own, achalazion may be injected with corticosteroid or be surgically removed.

Hordeola include both external hordeolum, or “stye”, and internalhordeolum (acute meibomianitis). Styes are lesions at the base of theeyelashes and are predominantly caused by infection of Staphylococcusaureus. Treatment may involve draining and topical application of anantibiotic to the lesion.

Infections may afflict the lacrimal system of the eye, such ascanaliculitis and dacrocystitis. Canaliculitis can be caused byActinomyces infection and treatment typically involves mechanicalexpression of the exudative or granular material from the canaliculi,combined with probing and irrigation of the nasolacrimal system with apenicillin eyedrop solution. Dacrocystitis is often due to streptococcior Staphylococcus aureus and is usually treated with antibiotics.

Rhinitis, an inflammation of the nasal mucous membrane, may producenasal decongestion and rhinorrhea. Rhinitis is typically of viralorigin, but may involve secondary bacterial infection. Acute rhinitismay be treated for symptoms, for example, with decongestants such aspseudoephedrine. Where bacterial superinfection is involved, antibioticsmay be administered.

Rhinorrhea and nasal congestion are typically of viral or allergicorigin. In certain instances, congestion is observed as an after-effectof topical decongestants (rhinitis medicamentosa). Allergic congestionand rhinorrhea are treated with antihistamines. While topical or oraldecongestants (e.g., pseudoephedrine) can provide some symptomaticrelief, prolonged use is not recommended.

Otitis media, inflammation of the middle ear structures, can lead toloss of equilibrium and deafness. Otitis media is generally of bacterialor viral origin. Viral infections may spawn secondary bacterialinfections, including infections of Streptococcus pneumonia, Moraxellacatarrhalis, and non-typable Haemophilus influenzae. Where bacterialinfection is suspected, the condition may be treated with antibiotics,as well as analgesics.

External otitis is an acute or chronic inflammation of the external earcanal, and may involve bacterial (e.g., Pseudomonas aeruginosa, Proteusvulgaris, and Staphylococcus aureus) or fungal (e.g., Aspergillus andCandida) infection. External otitis may be treated with, for example,antibiotics and corticosteroids.

Pharyngitis (sore throat) is characterized by pain and swelling in theposterior pharynx. Pharyngitis is commonly caused by bacterial (e.g.,Streptococcal) or viral infection, and may be treated with topicalanesthetics.

Stomatitis is a painful ulcer or inflammation of the oral mucosa.Stomatitis may be caused, for example, by infection (bacterial, viral,or fungal), chemical irritant, or allergic reaction, and may be commonfor patients having Xerostomia. Some common infectious agents includeherpes simplex virus, varicella zoster, Epstein-Barr virus, influenza,cytomegalovirus, Gonorrhea, and Candida. Treatments for stomatitisinclude anesthetics, corticosteroids, antihistamines, and/orantibiotics.

It is an object of the invention to provide a broadly effective and safetreatment for conditions characterized by infection (bacterial, viral,or fungal), and/or inflammation (including acute and chronicinflammation, as well as delayed-type and immediate-typehypersensitivity), so as to avoid development of bacterial resistance toantibiotics, and so as to avoid toxicity, irritation, and/orhypersensitivity that may occur with conventional agents.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a method for treating acondition involving infection and/or inflammation, including acute andchronic inflammation, as well as delayed-type and immediate-typehypersensitivity. Such conditions include ocular conditions, such asthose affecting the conjunctiva, uvea, eye lids, oil glands, andlacrimal ducts, such as: bacterial, viral, or allergic conjunctivitis,uveitis, blepharitis, external and internal hordeolum, canaliculitis,dacrocystitis, and chalazions. Such conditions also include variousconditions affecting the ear (including the inner ear, middle ear, earcanal, and ear drum), nose, mouth and throat, including rhinitis,sinusitis, rhinorrhea, otitis media, external otitis, myringitis,pharyngitis, and stomatitis.

The invention involves administering a hypohalous acid, such as HOCl, tothe affected area as described herein. The invention provides a broadlyeffective method for cleansing and treating the inflamed and/or infectedregions, and in a manner relatively independent of the etiology of theinflammation or infection, and in a manner that is free of toxicity andhypersensitivity. The method of the invention is useful as analternative or adjunct therapy to conventional antibiotics, antivirals,decongestants, antihistamines, and steroid treatments, or as analternative to therapy using a combination of conventional medicaments.

In a second aspect, the present invention provides a compositioncontaining hypohalous acid for treating inflamed and/or infected regionsof the eye, ear, nose (including sinuses), or throat. In an exemplaryembodiment, the composition is an electrolyzed saline solutioncomprising hypohalous acid, or consisting essentially of a hypohalousacid, as an active agent, and a pharmaceutically acceptable carrier. Theelectrolyzed solution may have a pH of from about 4 to about 7 and anavailable free chlorine (AFC) content of from about 20 to about 1000parts per million (ppm). The composition of the invention is broadlyeffective for cleansing, disinfecting, and/or reducing inflammation ofthe eyes, ears, nose, mouth, and/or throat. The composition of theinvention is useful as an alternative or adjunct to conventionaltreatments, and is particularly suitable for prolonged use and hygiene,especially for individuals prone to such infections and/or inflammatoryconditions, or individuals that typically experience hypersensitivitywith other treatments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic outline of the main processing stages forproducing an electrolyzed saline solution in accordance with certainembodiments of the present invention.

FIG. 2 is a flow diagram depicting the production of an electrolyzedsaline solution for in accordance with certain embodiments of thepresent invention.

FIG. 3 is a schematic illustration of an electrochemical cell that maybe used to produce an electrolyzed saline solution.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compositions and methods for treating acondition characterized by infection and/or inflammation, such asconditions of the eyes, ears, nose, mouth, and/or throat, byadministering a hypohalous acid, such as HOCl, to the affected area asdescribed herein.

Hypohalous Acid, Solutions, and Compositions

Hypochlorous acid (HOCl) is an oxidant and biocide that is produced bythe human body's natural immune system. HOCl is generated as the finalstep of the Oxidative Burst Pathway, with large quantities of HOCl beingreleased into phagocytic vesicles to destroy invading microorganisms. Itis considered, without wishing to be bound by any theory, thathypochlorous acid exerts a biocidal effect by attacking the surface andplasma membrane proteins, impairing transport of solutes and the saltbalance of bacterial cells (Pieterson et al, Water SA, 22(1): 43-48(1996)). In accordance with the present invention, exogenous hypohalousacid is administered for treating or preventing conditions characterizedby infection and/or inflammation. The compositions of the invention arenon-irritating and non-sensitizing to the skin, non-irritating to theeyes, not harmful if swallowed, show no evidence of mutagenic activity,and are safe for routine or prolonged use. An added advantage is thatthere is no resistance or tolerance developed by the microorganisms, asoccurs with the use of conventional antibiotics, and there is generallyno hypersensitivity as occurs with some agents conventionallyadministered to treat microbial infections and inflammatory conditions.

The hypohalous acid solution may be generated by electrolysis of salt,such as saline (NaCl), and may contain a mixture of oxidizing speciessuch as predominantly hypochlorous acid (HOCl) and sodium hypochlorite.Hypochlorous acid and hypochlorite are in equilibrium and the positionof the equilibrium is determined solely by the pH, which may becontrolled by the electrochemical generator. The hypohalous acidsolution may have a pH of from about 4 to about 7, but in certainembodiments has a pH of from about 5 to about 7, or from about 5.0 toabout 6.5, or from about 5.4 to about 5.8. For example, the hypohalousacid solution may have a pH of about 5.4. The pH of the solution can becontrolled, for example, by modulating the chemical properties of thesolution, or (where an electrolyzed solution is used as the source ofhypohalous acid) the hydraulic regime within the electrochemical cellsystem, the applied electric current, or the recirculation of thecatholyte produced by the electrochemical cell.

In certain embodiments, the electrolyzed solution consists ofessentially hypohalous acid as the active agent (e.g., HOCl), but incertain other embodiments may contain, or may also contain, otheroxidizing or radical producing species such as a hypohalite (e.g.,hypochlorite), hydroxide, H₂O₂ and O₃. These species may provideadditional biocidal activity, and may have additional benefits forclearing bacterial debris, biofilm, or discharge, such as where thehypohalous acid solution is used for treating ear infections, bacterialconjunctivitis or for cleaning or storing contact lenses. In certainembodiments, the hypohalous acid solution contains at least 80%hypohalous acid relative to the total concentration of hypohalous acid,hypohalite, and Cl₂ (as 100%). The hypohalous acid may have, however, atleast 90%, at least 95%, or at least 98% hypohalous acid. Suchembodiments may allow for higher levels of active chlorine to beadministered, while avoiding any irritation as a result of the solution.

The hypohalous acid solution, such as an HOCl solution, prepared byelectrolysis of salt or saline, contains an available free chlorine(AFC) content of from about 5 to about 1000 parts per million. Thedesired AFC content may be controlled by an apparatus as describedherein. In some embodiments, the solution of the invention has an AFCcontent of less than about 250 parts per million. For example, thesolution may have an AFC content of from about 20 to about 200 ppm, suchas from about 100 to about 200 ppm, or of from about 50 to about 100ppm, or from about 20 to about 50 ppm. Such solutions may beparticularly suited for routine use and/or prophylactic care, includingroutine cleansing and hygiene. In certain other embodiments, thesolution has an AFC content of greater than about 250 ppm. For example,the solution may have an AFC content of from about 250 to about 600 ppm,or from about 250 to about 400 ppm, or from about 400 to about 500 ppm,or from about 500 to about 600 ppm. While such solutions are potentbiocides, and may help reduce and control inflammation, includingimmediate-type hypersensitivity reactions, such solutions are notgenerally irritating to the skin, eye, nasal mucosa, and ear, and arenot harmful to contact lenses.

The electrolyzed solution of the invention may also contain from about0.2 to 2.0% w/v salt, such as NaCl. In some embodiments, the inventioncontains 0.4 to 1.5% w/v salt, or may be a normal saline solution (0.9%w/v NaCl). In some embodiments, the solution is isotonic withphysiological fluids, such blood, saliva or tears. While the hypohaloussolution may be administered at room temperature, the solution mayalternatively be heated, for example, to body temperature or about bodytemperature, or above body temperature to help drain fluids from thesite of infection as well as loosen oils that spawn infection. Incertain embodiments, the hypohalous acid is administered at below bodytemperature. Such embodiments may be particularly suited to controlacute inflammation.

The hypohalous acid may be prepared by electrolysis of one or morehalide salts, including Cl, Br, I, F, and At. Thus, the hypohalous acidmay include one or a mixture of HOC1, HOBr, HOI, HOF, and HOAt. Incertain embodiments, the electrolyzed solution is generated using amixture of physiologically balanced salts, as disclosed in U.S. Pat. No.6,426,066, which is hereby incorporated by reference in its entirety.Such salts may include sodium halides (e.g., NaCl), potassium halides(e.g., KCl) and magnesium halides (e.g., MgCl₂).

While the composition of the invention may be formulated as a liquid,such as an eye drop, eye wash, wash for contact lenses, gargle, nasal orthroat spray, or ear drop, the composition may alternatively take theform of a cream, gel, and/or foam for application to the skinsurrounding the eye. Such formulations may be prepared using conventionadditives known in the art and/or as described herein. In embodimentsemploying creams, gels, and/or foams, the solution is better containedaround the site of infection or inflammation by limiting run-off.Convenient applicators for creams, foams, and the like are known, andmay be used in accordance with the present invention. Alternativelystill, the composition of the invention may be formulated so as to bedelivered by aerosol, mist, or steam.

The electrolyzed solution may have an oxidation reduction potential(redox) of greater than about +650 mV, greater than about +950 mV, suchas about +1000 mV. A high redox potential allows for the quick andefficient destruction of microbes (bacteria, viruses, fungi and spores).In certain embodiments of the invention, the hypohalous acid solutionhas a biocide rate (D Value) of approximately 1 log reduction ofBacillus subtilis spores in less than 1 minute with a 9:1 electrolyzedsolution: innoculum mix. In some embodiments, the solution has a biociderate of as low as 3.4 seconds. Generally, the hypohalous acid iseffective on a broad spectrum of bacterial, fungal, and viral pathogens.

In certain embodiments of the present invention, the hypohalous acid isformulated or administered in combination with another therapeuticagent. Non-limiting examples of therapeutic agents includeanti-microbial agents such as antibiotics, anti-inflammatory agents,anti-histamines, analgesics, anti-oxidants such as vitamins, andmoisturizing agents. For example, the hypohalous acid may be formulatedor administered with bacitracin, neomycin, neosporin, framycetin,fusidic acid, corticosteroid, chloramphenicol, gentamicin, tobramycin,ceftriaxone, sulfacetamide, erythromycin, gentamicin, ciprofloxacin,ofloxacin, cefoxitin, cefotaxime, spectinomycin, tetracycline,doxycycline, azithromycin, and/or acyclovir.

The composition may comprise a pharmaceutically acceptable carrier.Non-limiting examples of suitable carriers include polyvinyl alcohol,povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethylcellulose, hydroxyethyl cellulose, and purified water. The compositionsof the present invention may also include various other ingredients,such as tonicity agents, buffers, surfactants, co-solvents, viscositybuilding agents, preservatives, and other therapeutic agents.

Regarding tonicity agents, such agents may be employed to adjust thetonicity of a composition, for example, in the case of an ophthalmiccomposition, to the tonicity of natural tears. For example, sodiumchloride, potassium chloride, magnesium chloride, calcium chloride,dextrose and/or mannitol may be added to the composition to approximatephysiological tonicity. Such an amount of tonicity agent will vary,depending on the particular agent to be added and the type ofcomposition. In general, however, the compositions will have a tonicityagent in an amount sufficient to cause the final composition to have anacceptable osmolality. For example, for an ophthalmic composition, thecomposition generally about 150 to 450 mOsm, preferably 250 to 350 mOsm.

Regarding buffers, an appropriate buffer system (such as, for example,sodium phosphate, sodium acetate, sodium citrate, sodium borate or boricacid) may be added to the compositions to prevent pH drift under storageconditions. The particular concentration will vary, depending on theagent employed. Preferably, however, the buffer will be chosen tomaintain a target pH within the range of pH 4-7 or a range as describedherein.

Regarding a surfactant, various surfactants useful in conventionalformulations may be employed. Exemplary surfactants include Cremophor®EL, polyoxyl 20 ceto stearyl ether, polyoxyl 40 hydrogenated castor oil,polyoxyl 23 lauryl ether and poloxamer 407.

Regarding viscosity building agents, such agents may be added tocompositions of embodiments of the present invention to increase theviscosity of the carrier. Examples of viscosity enhancing agentsinclude, but are not limited to: polysaccharides, such as hyaluronicacid and its salts, chondroitin sulfate and its salts, dextrans, variouspolymers of the cellulose family; vinyl polymers; and acrylic acidpolymers. For example, the composition may exhibit a viscosity of 1 to400 centipoises (“cps”).

Regarding preservatives, suitable preservatives include benzalkoniumchloride, chlorobutanol, benzododecinium bromide, methyl paraben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid,polyquaternium-1, or other agents known to those skilled in the art. Inaddition, the composition of the present invention may includeantimicrobial agents such as antibacterials to provide safety andefficacy for storage stability. The amount of antibacterial can bewithin the range of from about 0.004% to about 0.5% by weight/volume ofthe composition. A suitable antibacterial would include, for example,from about 0.004% to about 0.02% by weight/volume of benzalkoniumchloride, from about 0.25% to about 0.5% of chlorobutanol, about 0.1% ofthimerosal, about 0.05% methylbaraben, about 0.01% propylbaraben, andsodium chloride in an amount sufficient to make an isotonic solution.The composition can also include other therapeutic agents such asanti-inflammatory agents, antihistamines, decongestants, antibiotics,and/or moisturizing agents known in the art.

Ocular Conditions

In certain embodiments, the present invention relates to treating anocular condition, especially an ocular condition(s) originating from aninfection and/or inflammatory condition. The ocular condition may affectany portion of the eye or surrounding areas, such as the conjunctiva,uvea, eyelid, oil glands, and lacrimal ducts. Exemplary ocularconditions include: red eye; dry eye (including dry eye syndrome);conjunctivitis of bacterial, viral, or allergic origin; uveitis,blepharitis; external or internal hordeolum; canaliculitis;dacrocystitis; and chalazions. The ocular condition may be present in ahuman or animal patient. Exemplary animal patients include mammals suchas dogs, cats, horses, lamb, cattle, goats, pigs, and guinea pigs. Thepresent invention further contemplates preventive care for such ocularconditions.

The invention includes the treatment and prevention of ocular infectionscaused by a variety of pathogens, such as, for example, a bacterialagent, a viral agent, a parasitic agent, and/or a fungal agent.Non-limiting examples of bacterial agents include Streptococcus spp.(e.g. pneumoniae), Staphylococcus spp. (e.g., aureus), Haemophilus spp.(e.g., influenzae), Pseudomonas spp. (e.g., aeuruginosa), Chlamydia spp.(e.g., trachomatis, psittaci, pecorum), Neisseria spp. (e.g.gonorrhoeae), and Actinomyces species. Non-limiting examples of viralagents include adenovirus, respiratory syncytial virus (RSV), influenza(including parainfluenza), coxackie virus, rhinovirus, coronavirus, andherpes simplex virus. Non-limiting examples of fungal agents includeCandida species, Fusariu species, and Aspergillus species. Anon-limiting example of a parasitic agent is an eyeworm. Certainbacterial agents may be more common in certain patient subpopulations.For example, different strains of Chlamydia psittaci and Chlamydiapecorum cause significant eye infection in cats, lambs, goats, andguinea pigs. These infections are occasionally transmitted to humans.Further, eyeworms are common parasites of horses and cattle, goats,pigs, dogs and cats.

These microbial agents may be involved in various ocular infectionsincluding blepharitis; hordeola, such as external hordeolum and internalhordeolum; conjunctivitis, such as viral conjunctivitis or bacterialconjunctivitis, conjunctivitis in newborns (opthalmia neonatorum) due toChlamydia trachomatis or Neisseria gonorrhoeae, chlamydial disease inadults such as inclusion conjunctivitis and trachoma, or gonococcalconjunctivitis in adults; iridocyclitis and panopthalmitis caused byBacillus subtilis; lacrimal system infections such as canaliculitis anddacrocystitis; keratitis, such as viral keratitis (herpes simplexvirus), bacterial keratitis and fungal keratitis (e.g., Fusarium),including among soft contact lens wearers; toxoplasmosis, including indogs and cats; feline herpes virus, which is a common cause of eye andupper respiratory infections in cats; uveitis, including in largeanimals, such as cattle, caused by Listeria; and eye infections causedby avian flu or other eye conditions and infections secondary to othermedical conditions.

In certain embodiments of the invention, the ocular condition involves abacterial infection that is antibiotic resistant. For example, thebacterial infection may be resistant to antibiotics commonly employed tocombat eye infections either topically or systemically, such assulfacetamide, erythromycin, gentamicin, ciprofloxacin, ofloxacin,cefoxitin, ceftriaxone, cefotaxime, spectinomycin, tetracycline,doxycycline, azithromycin, or bacitracin. In these and otherembodiments, the bacterial invention may be resistant to beta-lactamantibiotics or fluoroquinolones. For example, the infection may involvemethicillin-resistant Staphylococcus aureus (MRSA), for which thepresent invention is effective.

In certain embodiments, the ocular condition involves a viral infection,which may further include a secondary bacterial infection, such thatconventional antibiotic treatment is necessarily insufficient.

In certain embodiments, the ocular condition may be a bacterialinfection that produces a discharge that hinders vision and/or eyefunction, such as bacterial conjunctivitis. In these embodiments, theinvention provides the benefit of effectively cleaning sticky discharge,biofilm, or debris from the eye in a manner that reduces the risk ofspreading the infection to an unaffected eye or another individual.Where the condition involves biofilm, the hypohalous acid deactivatesthe polymatrix material of the biofilm to facilitate removal(cleansing), and disinfection. Hypohalous acid contact with biofilmformation dissolves the protective polysaccharaide matrix of the biofilmaiding in the effective removal of pathogens and debris.

In certain embodiments, the ocular condition involves an inflammatorydisorder or hypersensitivity reaction (including types I, II, III,and/or IV). For example, the ocular condition may involve animmediate-type hypersensitivity reaction such as allergicconjunctivitis. In other embodiments, the condition may result from ablocked gland or chronic inflammatory condition, including styes andchalazions, which may also develop an acute bacterial infection. Suchconditions may be recurring or may be difficult to completely clear.Other inflammatory ocular conditions that may or may not involvemicrobial infection, include uveitis.

In certain embodiments, the ocular condition is prevention of infectionand/or inflammation resulting from an eye surgery.

Modes of Treatment For Ocular Conditions

Treating an ocular condition in accordance with the present inventiongenerally involves alleviating the cause or symptoms of the condition,and can include: reducing inflammation or hypersensitivity in the eye orsurrounding area; reducing irritation in the eye or surrounding area;reducing redness in the eye; reducing discharge from the eye; improvingvision from the eye; clearing a microbial infection; preventing, orreducing the spread of a microbial infection, including the spread ofinfection from the infected eye to an uninfected eye; and moisturizingor reducing dryness of the eye. These can be measured or determined bycomparing the patient's condition prior to and after treatment withhypohalous acid in accordance with the present invention. Alternatively,treatment can be determined relative to a patient having the same orsimilar condition who has not been treated with the hypohalous acid inaccordance with the present invention. In certain embodiments, theadministration of hypohalous acid treats both an infection andinflammation, such as acute or chronic inflammation, associated with anocular condition.

In certain other embodiments, the hypohalous acid is administeredprophylacticly, especially where eye infections are likely to occur orbe transmitted among persons. Thus, in this embodiment, the inventioninvolves administering the hypohalous acid before an infection develops.Such prophylactic care might include routine cleaning of the eyes andsurrounding areas, such as the eyelids, with the hypohalous acid, orroutine rinsing of contact lenses by applying the hypohalous acid to thecontact lenses to decontaminate and clear debris and biofilm. Suchembodiments can result in the prevention of an ocular infection, canprevent the worsening of an existing ocular infection caused bycontaminated lenses, or can prevent irritation of the eyes caused bybacterial biofilm. In other embodiments, the invention involvesadministering hypohalous acid to the environment via fogging, misting,or humidifying, to prevent the transfer of pathogens from air dropletsinto the eyes of susceptible individuals.

In certain embodiments of the invention, the ocular condition involves abacterial infection that is antibiotic resistant. For example, thebacterial infection may be resistant to antibiotics commonly employed tocombat eye infections either topically or systemically, such assulfacetamide, erythromycin, gentamicin, ciprofloxacin, ofloxacin,cefoxitin, ceftriaxone, cefotaxime, spectinomycin, tetracycline,doxycycline, azithromycin, or bacitracin. In these and otherembodiments, the bacterial invention may be resistant to beta-lactamantibiotics or fluoroquinolones. In these embodiments, the hypohalousacid of the invention may be administered after unsuccessful topical orsystemic antibiotic treatment. For example, where the invention reoccursor is generally unaffected by antibiotic treatment, hypohalous acid maybe administered to the affected regions has discussed herein, withoutfurther investigation as to the causative agent where not practical. Instill other embodiments, the hypohalous acid may be administered to theaffected regions in place of antibiotic treatment, thus makingantibiotic treatment unnecessary. For example, administering hypohalousacid in accordance with the present invention may be used as analternative to administration of a beta-lactam or fluoroquinoloneantibiotic, thereby avoiding the hypersensitivity reactions common withsuch drugs. This embodiment is particularly advantageous whereantibiotic resistance has already been developed by the microorganism,the hypohalous acid being an alternative to potential “last lines ofdefense” with antibiotic treatment, since resistance will not bedeveloped to the hypohalous acid, and no further resistance toconventional antibiotics will then be cultivated.

In certain embodiments, the invention is a superinfection, includingboth viral and bacterial etiology. In such embodiments, the hypohalousacid may be administered in place of other agents or combinationtherapies, to treat and or help clear the various microbial pathogens.

The hypohalous acid may also be used as an adjunct cleanser along withantibiotic or steroidal treatment to provide synergistic disinfectingand/or anti-inflammatory effects. For example, when used in conjunctionwith an antibiotic, the treatment provides a potent antimicrobialeffect, while avoiding or limiting the development of antibioticresistance. This aspect of the infection is particularly useful wherethe infection is chronic or recurring, since continued or repeatedantibiotic treatment is generally not accepted.

In certain embodiments, the ocular condition may be a bacterialinfection that produces a discharge that hinders vision and/or eyefunction, such as bacterial conjunctivitis. In these embodiments,cleaning the eye and the surrounding areas with the hypohalous acid ofthe invention provides the benefit of effectively cleaning debris,biofilm, and/or discharge from the eye in a manner that reduces the riskof spreading the infection to an unaffected eye or another individual.

In certain embodiments, the ocular condition may result from an acute orchronic inflammatory condition, which may develop an acute infection. Inthese embodiments, the hypohalous acid is administered to treat both theinfection and the underlying inflammation. Thus, the hypohalous acid maybe administered instead of steroidal drops or systemic steroidalmedications, or antibiotics, thereby avoiding the potential adversereactions of such treatments. In certain other embodiments, thehypohalous acid is used to clean the region during the duration ofsteroidal and/or antibiotic treatment. In one embodiment, hypohalousacid is administered to the eye of a patient inflicted with uveitis,during the duration of steroid treatment. For example, the hypohalousacid may be used in conjunction with glucocorticoid steroids, either astopical eye drops (such as betamethasone, dexamethasone or prednisolone)or oral therapy with prednisolone tablets. Likewise, when the conditionhas an allergic origin, such as allergic conjunctivitis, the hypohalousacid may be used alongside an antihistamine to more effectively inhibitrelease of inflammatory mediators from mast cells.

In certain embodiments of the present invention, the hypohalous acidsolution is administered with treatment using a warm compress,especially where the condition is blepharitis, an external hordeolum, aninternal nordeolum, or a chalazion. In these embodiments, the hypohalousacid may be used for routine cleansing of the affected area for theduration of the treatment, and after treatment to avoid recurrence ofthe condition.

In certain embodiments, the hypohalous acid solution may be administeredto two or more sites in the ocular system of a patient. For example, thehypohalous acid may be administered as drops to the eye or eye wash, andas a cleanser for the eye lids and/or eyelid margins.

In another embodiment, the hypohalous acid treatment is followed bytreatment with an antioxidant, such as a vitamin.

The hypohalous acid and compositions of the present invention may beadministered in any appropriate dosage form such as a liquid, aerosol,gas, or semi-solid including a solution, suspension, viscous orsemi-viscous gel, ointment, cream, or other types of compositions.Preferably, the solution is administered topically either dropwise intothe eye or to the tissue surrounding the eye. The solution orcomposition comprising the solution can also be formulated into asterile solution for administration by intracameral injection into theanterior chamber of the eye or directly into the trabecular meshwork ofthe eye. The doses used for the above described purposes can bedetermined by a physician or other qualified medical personnel and candepend, for example, on the type of ocular condition, the frequency ofadministration (i.e. for chronic or acute use), the severity of thecondition, the age and overall health of the patient, the dosage form ofthe hypohalous acid, and other factors. For example, in one non-limitingembodiment, 1 to 2 drops of an electrolyzed saline solution isadministered 1 to 10 times per day. In another embodiment, the solutionis administered 1 to 4 times per day.

For chronic or routine use, one to two drops of the solution can beadministered once or twice daily, similar to artificial tears. Onenon-limiting example of a chronic indication is using hypohalous aciddrops for dry eyes or for rinsing or storing contact lenses. Thehypohalous acid drops may be used to sooth/bath eyes from everyday wearand tear, such as, for example, from computer screen glare, dust andother environmental contaminants, exposure to air-conditioning, generaldryness and other causes. The AFC concentration of the hypohalous acidsolution may vary depending on whether the solution is used chronicallyor acutely. For example, for chronic use, the AFC concentration may beon relatively low. For example, in certain embodiments, the AFCconcentration is from about 5 to about 100 ppm, such as from about 5 toabout 20 ppm. For acute use, such as an acute microbial infection, theAFC concentration should be sufficient to kill or reduce bacteriaassociated with the infection. Thus, for acute uses, the AFCconcentration may be relatively high. For example, in certainembodiments, the AFC concentration is from about 200 to about 650 ppm.In certain other embodiments, the AFC concentration is from about 200 toabout 400 ppm.

Conditions of the Ears, Nose, and Throat

The present invention provides treatments as well as preventive care forconditions characterized by infection and/or inflammation of the ears(including the outer ear, middle ear, and inner ear), nose (includingsinus care), mouth, and throat. Exemplary conditions include: rhinitis,rhinorrhea, nasal congestion, otitis media, external otitis,pharyngitis, and stomatitis, and may be present in a human or animalpatient. Exemplary animal patients include mammals such as dogs, cats,horses, lamb, cattle, goats, pigs, and guinea pigs. The presentinvention further provides preventive care for such conditions,especially where such conditions are recurring, such as recurring earinfection, sinus infection, sore throat, or mouth ulcer.

In these embodiments, the invention includes the treatment andprevention of infections caused by a variety of pathogens, such as, forexample, a bacterial agent, a viral agent, a parasitic agent, and/or afungal agent. Non-limiting examples of bacterial agents includeStreptococcus spp. (e.g. pneumoniae), Staphylococcus spp. (e.g., aureusincluding MRSA), Haemophilus spp. (e.g., influenzae), Moraxella spp.,Pseudomonas spp. (e.g., aeuruginosa), Chlamydia spp. (e.g., trachomatis,psittaci, pecorum), Neisseria spp. (e.g. meningiditis), Mycobacterium,and Actinomyces species. Non-limiting examples of viral agents includeadenovirus, respiratory syncytial virus (RSV), influenza (includingparainfluenza and avian flu), coxackie virus, rhinovirus, coronavirus,varicella zoster, and herpes simplex virus. Non-limiting examples offungal agents include Candida species, Fusariu species, and Aspergillusspecies.

In certain embodiments of the invention, the condition of the ear, nose,mouth, and/or throat involves a bacterial infection that is antibioticresistant. For example, the bacterial infection may be resistant toantibiotics commonly employed to combat such infections either topicallyor systemically, such as sulfacetamide, erythromycin, gentamicin,ciprofloxacin, ofloxacin, cefoxitin, ceftriaxone, cefotaxime,spectinomycin, tetracycline, doxycycline, azithromycin, or bacitracin.In these and other embodiments, the bacterial invention may be resistantto beta-lactam antibiotics or fluoroquinolones. For example, theinfection may involve methicillin-resistant Staphylococcus aureus(MRSA), for which the present invention is effective. Further, theinvention may help control the presence and/or spread of MRSA in andfrom colonized individuals, that is, where no obvious infection ispresent. Thus, in some embodiments, the hypohalous acid is employedafter antibiotic treatment to kill resistant pathogens, despite noremaining signs of infection.

In certain embodiments, the condition involves a viral infection withsecondary bacterial infection (which may be antibiotic resistant), suchthat conventional antibiotic treatment is necessarily insufficient. Forexample, the condition may be a sinus infection or ear infection ofviral origin, which has developed a bacterial superinfection. Unlikeconvention antibiotics, the invention has benefit in controlling andclearing both the viral and bacterial components of the infection.

In certain embodiments, the condition may involve a bacterial infectionthat produces a discharge, for example, external otitis or otorrhea. Inthese embodiments, the hypohalous acid effectively cleans discharge,biofilm, or debris from the ear in a manner that reduces the risk ofspreading infection.

In certain embodiments, the condition involves an inflammatory disorderor hypersensitivity reaction (including types I, II, III, and/or IV).For example, the condition may involve an immediate-typehypersensitivity reaction such as allergic rhinitis or sinusitis. Inother embodiments, the condition may result from a chronic inflammatorycondition, which may also develop an acute bacterial infection. Suchconditions may be recurring or may be difficult to completely clear.

Modes of Treating Ear, Nose, Mouth, and Throat Conditions

Treating a condition of the ear, nose, mouth, and/or throat inaccordance with the present invention generally involves alleviating thecause or symptoms of the condition, and can include: reducinginflammation or hypersensitivity; reducing irritation; reducingdischarge; clearing a microbial infection; preventing, or reducing thespread of a microbial infection. These can be measured or determined bycomparing the patient's condition prior to and after treatment withhypohalous acid in accordance with the present invention. Alternatively,treatment can be determined relative to a patient having the same orsimilar condition who has not been treated with the hypohalous acid inaccordance with the present invention. In certain embodiments, theadministration of hypohalous acid treats both an infection andinflammation, such as acute or chronic inflammation.

In certain other embodiments, the hypohalous acid is administeredprophylacticly, especially where infections are likely to occur or betransmitted among persons. Thus, in this embodiment, the inventioninvolves administering the hypohalous acid before an infection develops.Such prophylactic care might include routine cleaning of the ear, mouth,throat, nose, or sinuses, with the hypohalous acid. Such embodiments canresult in the prevention of an infection, can prevent the worsening ofan existing infection, or can prevent irritation caused by bacterialbiofilm. In other embodiments, the invention involves administeringhypohalous acid to the environment via fogging, misting, or humidifying,to prevent the transfer of pathogens from air droplets into the ear,nasal passages, and oral cavity of susceptible individuals.

In certain embodiments of the invention, the condition involves abacterial infection that is antibiotic resistant. For example, thebacterial infection may be resistant to antibiotics commonly employed tocombat such infections either topically or systemically, such assulfacetamide, erythromycin, gentamicin, ciprofloxacin, ofloxacin,cefoxitin, ceftriaxone, cefotaxime, spectinomycin, tetracycline,doxycycline, azithromycin, or bacitracin. In these and otherembodiments, the bacterial invention may be resistant to beta-lactamantibiotics or fluoroquinolones. In these embodiments, the hypohalousacid of the invention may be administered after unsuccessful topical orsystemic antibiotic treatment. For example, where the invention reoccursor is generally unaffected by antibiotic treatment, hypohalous acid maybe administered to the affected regions has discussed herein, withoutfurther investigation as to the causative agent where not practical. Instill other embodiments, the hypohalous acid may be administered to theaffected regions in place of antibiotic treatment, thus makingantibiotic treatment unnecessary. For example, administering hypohalousacid in accordance with the present invention may be used as analternative to administration of a beta-lactam or fluoroquinoloneantibiotic, thereby avoiding the hypersensitivity reactions common withsuch drugs. This embodiment is particularly advantageous whereantibiotic resistance has already been developed by the microorganism,the hypohalous acid being an alternative to potential “last lines ofdefense” with antibiotic treatment, since resistance will not bedeveloped to the hypohalous acid, and no further resistance toconventional antibiotics will then be cultivated.

In certain embodiments, the invention is a superinfection, including ofboth viral and bacterial etiology. In such embodiments, the hypohalousacid may be administered in place of other agents or combinationtherapies, to treat and or help clear the various microbial pathogens.

The hypohalous acid may also be used as an adjunct cleanser along withantibiotic or steroidal treatment to provide synergistic disinfectingand/or anti-inflammatory effects. For example, when used in conjunctionwith an antibiotic, the treatment provides a potent antimicrobialeffect, while avoiding or limiting the development of antibioticresistance. This aspect of the infection is particularly useful wherethe infection is chronic or recurring, since continued or repeatedantibiotic treatment is generally not accepted.

In certain embodiments, the condition may be a bacterial infection thatproduces a discharge, such as an ear or sinus infection. In theseembodiments, cleaning the middle ear, ear canal, or sinuses, forexample, with the hypohalous acid of the invention provides the benefitof effectively cleaning wax, debris, biofilm, and/or discharge in amanner that reduces the risk of spreading the infection to anotherindividual. Where the condition involves biofilm, the hypohalous aciddeactivates the polymatrix material of the biofilm to facilitate removal(cleansing), and disinfection. Hypohalous acid contact with biofilmformation dissolves the protective polysaccharaide matrix of the biofilmaiding in the effective removal of pathogens and debris.

In certain embodiments, the condition may result from an acute orchronic inflammatory condition, which may develop an acute infection. Inthese embodiments, the hypohalous acid is administered to treat both theinfection and the underlying inflammation. Thus, the hypohalous acid maybe administered instead of steroidal drops or systemic steroidalmedications, or antibiotics, thereby avoiding the potential adversereactions of such treatments. In certain other embodiments, thehypohalous acid is used to clean the region during the duration ofsteroidal and/or antibiotic treatment. In one embodiment, hypohalousacid is administered to the nasal passages and/or sinuses of an allergicpatient, during the duration of steroid treatment. For example, thehypohalous acid may be used in conjunction with steroid treatment, oralongside an antihistamine to more effectively inhibit release ofinflammatory mediators from mast cells.

The hypohalous acid and compositions of the present invention may beadministered in any appropriate dosage form such as a liquid, aerosol,or semi-solid including a solution, suspension, gas, viscous orsemi-viscous gel, ointment, cream, or other types of compositions. Suchcompositions include nasal sprays, throat sprays, and mouth wash. Thedoses used for the above described purposes can be determined by aphysician or other qualified medical personnel and can depend, forexample, on the type of condition, the frequency of administration (i.e.for chronic or acute use), the severity of the condition, the age andoverall health of the patient, the dosage form of the hypohalous acid,and other factors. For example, in one non-limiting embodiment, 1 to 2drops of the hypohalous acid solution is administered 1 to 10 times perday. In another embodiment, the solution is administered 1 to 4 timesper day.

For chronic or routine use, one to two drops of the solution can beadministered once or twice daily. The AFC concentration of thehypohalous acid solution may vary depending on whether the solution isused chronically or acutely. For example, for chronic use, the AFCconcentration may be on the lower end of a range from 5 to 1000. Forexample, in certain embodiments, the AFC concentration is from about 5to about 100 ppm, such as from about 5 to about 20 ppm. For acute use,such as an acute microbial infection, the AFC concentration should besufficient to kill or reduce bacteria associated with the infection. TheAFC concentration is preferably on the higher end of a range from 5 to1000 ppm. For example, in certain embodiments, the AFC concentration isfrom about 200 to about 650 ppm. In certain other embodiments, the AFCconcentration is from about 200 to about 400 ppm.

For patients afflicted with a sinus infection and/or allergic condition,the present invention provides for administration of the hypohalous acidas described herein to the nose and/or sinus cavity. In theseembodiments, the invention provides a broadly effective and safetreatment for sinus conditions characterized by infection and/orinflammation (including immediate-type hypersensitivity), so as to avoiddevelopment of bacterial resistance to antibiotics, and so as to avoidtoxicity, adverse effects, irritation, and/or hypersensitivity that mayoccur with other agents including antihistamines. In these embodiments,the hypohalous acid as described herein may be administered to the noseor sinuses of an affected patient as an alternative or adjunct therapyto antibiotics and/or antihistamines, or other convention treatment,depending on the suspected etiology of the condition. In accordance withthese embodiments, the hypohalous acid may be administered as a nasalspray using conventional formulation as described in U.S. Pat. No.6,565,832, for example, which is hereby incorporated by reference in itsentirety.

In another embodiment, the hypohalous acid treatment is followed bytreatment with an antioxidant, such as a vitamin.

Production of Hypohalous Acid and Compositions of the Invention

The hypohalous acid solution for use in the methods and compositions ofthe present invention may be prepared by electrolysis of a saltsolution. Exemplary methods and apparatuses for preparing electrolyzedsolutions are disclosed in US published patent application no.2004/0060815, which is hereby incorporated by reference in its entirety.

In one embodiment, a salt solution (electrolyte) may be pre-packaged andprovided for preparing the hypohalous acid solution on demand byelectrolysis. In other embodiments, the electrolyte may be provided indry form, and mixed with de-ionized and/or softened water to prepare thehypohalous acid on demand.

FIG. 1 provides a schematic outline of the main processing stages of anon-limiting, exemplary method for producing an electrolyzed salinesolution. Such a method involves an input and pre-processing stage; aproduction stage; and a storage and dispensing stage. In the input andpre-processing stage, water can be passed through a water softener zonewhere excess magnesium and calcium ions are removed. The resultantsoftened water can be passed as process water to a brine generation zonewhere a salt (e.g., a halide salt such as NaCl and/or KCl) can be addedto produce a dilute salt solution. Preferably, the salt is vacuum driedcrystalline salt which is commercially produced to a consistentstandard. The dilute salt solution can be a substantially constantconcentration since a known quantity of salt is added to a knownquantity of softened water to achieve a desired concentration of thedilute salt solution. Another method may involve mixing a known amountof a salt, such as, for example, NaCl or KCl, with de-ionized orde-mineralized water. This water can be used as delivered by a deionizeror demineralizer or can be dosed with a known amount of a bufferingagent, such as, for example, sodium bicarbonate. This electrolyte canthen be introduced to the production stage.

In the production stage, the dilute saline solution or preparedelectrolyte can be passed to one or more electrolytic cell systems, suchas the electrolytic cell pack 63 depicted in FIG. 2 (a preferredembodiment of which is described in more detail in FIG. 3). Of course,other electrolytic systems can be used as well such as parallel discsand parallel plate systems. The electrochemical cell includes a cathodeand an anode chamber, across which a substantially constant electriccurrent is applied. The applied electric current can be maintainedconstant via an energy control and monitoring zone. Catholyte andanolyte are produced from the cathode and anode chambers respectively asa result of electrochemical treatment of the saline solution in thecells. Catholyte and anolyte can be prevented from mixing using aseparator. For example, a semi-permeable membrane can be used in thecase of parallel plate technology (for example, NAFION® membrane) or aporous ceramic membrane. In some embodiments, the catholyte is notrequired for the final solution and is directed to drain. In otherembodiments, all or part of the catholyte is re-introduced into theanode chamber (referred to in the art as catholyte recirculation).Catholyte that is not recirculated can be directed to waste, andanolyte, otherwise referred to as output solution, is passed to a bufferstorage and quality subsystem in the storage and dispensing stage. Theoutput solution can be tested in the buffer storage and qualitysubsystem, and, if it fails to meet the quality standards, can also bedirected to waste. If the output solution falls within specification,the output solution can be permitted to pass to an output solutionstorage zone from where it can be subsequently dispensed for use orpackaged.

FIG. 2 is a flow diagram or “hydraulic map” showing in more detail anexemplary method of producing an electrolyzed saline solution inaccordance with the present invention. Potable water can be passedthrough an external water softener containing a cation exchange resin(not shown) thereby exchanging hardness ions of calcium and magnesiumonto the resin and releasing sodium ions into the water. The softenedwater can be fed through a valve 16 into a softened water tank 14 whichmay include a plurality of level detectors for monitoring andcontrolling the softened water level. For example, tank 14 may include alevel detector 20, which is a safety device which is activated only whenthe softened water in tank 14 reaches a predetermined extra high levelto stop the charging of tank 14 with further softened water. Tank 14 mayalso include a level detector 22 which ensures that tank 14 has acorrect volume of softened water to prepare the appropriateconcentration of saline solution. Tank 14 may also include a leveldetector 26 and softened water will begin to re-charge tank 14 when thesoftened water drops below a predetermined low level determined by leveldetector 26 and at the end of production of one batch of electrolyzedsaline solution. Tank 14 may also include a valve 28 which allows liquidto be drained.

To produce a saline solution from the softened water in tank 14, a salt,such as, for example, vacuum dried crystalline salt can be added to tank14 via dispensing wheel 21. Dispensing wheel 21 contains many tablets ofknown salt mass, a pre-determined number of which are dispensed througha hole in the top of tank 14 at the start of each electrolyzed salinesolution production cycle. Preferably, the saline solution has a saltconcentration range of 2.0 to 90.0 g/L.

Pump 59 can pump the saline solution towards an electrolytic cell pack63. The flow rate of the saline solution can be monitored by a sensor10. The sensor can ascertain whether the incoming saline solution is ata temperature within the range under which the process can reasonablyoperate, such as between 5 and 35° C. Other parameters such as theincoming solution's pressure, softness, alkalinity, pH, conductivity,and microbial count can be monitored, modulated and/or controlled toestablish that the solution falls within acceptable levels for theprocess or for desired characteristics of the resulting solution. Forexample, as the salt concentration of the solution is increased, theconductivity can be increased and other parameters, such as the current,would change. The various parameters can be modified to correspond tothe desired salt concentration of the solution. A person of skill in theart can appreciate whether the incoming water is not suitable forprocessing according to embodiments of the present invention. If sensor10 detects that the properties of the incoming saline solution do notfall within acceptable limits, the solution can be diverted through awaste discharge manifold (not shown) to a drain via valve 12. On theother hand, if the incoming saline solution is acceptable, it can beallowed to flow into the cells through valve 13.

The saline solution can then split into two streams 58 and 60 beforebeing fed through electrochemical cell pack 63. In certain embodiments,electrochemical cell pack 63 can include eight electrolytic cells, withtwo sets of four cells connected hydraulically in parallel. Forsimplicity, only one cell is illustrated. In general, the number ofcells in the cell pack can be determined by the output volume requiredfrom the particular system. Each cell has an anode chamber and a cathodechamber and the flow of saline solution can be split such that thegreater portion is fed to the anode chamber and the lesser portion isfed to the cathode chamber. In certain embodiments, approximately 90% ofthe saline solution can be passed through the anode chamber and theremainder can be passed through the cathode chamber. The flow rate ofsaline solution through the cathode chamber can be much lower than forthe anode chamber and the pressure in the cathode chamber can also belower. The flow rate of saline solution into the cathode chamber, whichalso has an influence on the pH of the output solution, can becontrolled by a flow regulator 68. Flow regulator 68 can be manuallyadjusted if there is a variation in input water quality.

In certain embodiments, the flow rate supplied to the anode is from 50%to 95%, inclusive of all intermediate values, of the solution applied tothe electrolytic cell pack 63. In certain embodiments, the flow rate tothe anode is from 85% to 95% of the solution supplied to theelectrolytic cell pack.

As the saline solution flows through the electrolytic cells, a fixedcurrent of from 0.1 to 25 amps, preferably 15 to 25 amps, and morepreferably 18-19 amps, can be applied to each cell causing electrolysisof the saline solution thereby generating available free chlorine in theresulting anolyte, elsewhere generally referred to as the outputsolution. In order to produce output solution at a certain pH, forexample between 5 and 7 (acidic to neutral), the pH of the outputsolution may be at least partially controlled by dosing a portion of thecatholyte to the inlet stream for the anode chambers. The catholyte maybe dosed to the inlet stream 58 by an adjustable pump and valve system66 and the dosing rate is increased or decreased to achieve the targetpH. The remaining catholyte which is not dosed into the input stream 58for the anode chambers can be directed to waste, if necessary dilutingit prior to disposal. As just described, in certain embodiments, thecatholyte can be dosed into the anode stream 58 before this streamenters the anode. However, the catholyte can also be dosed into theanode stream after it has been electrolyzed. In those application wherethe electrolyte is prepared by mixing the various salts with de-ionizedor de-mineralized water, mixing of the catholyte may not be performed,in which case all the catholyte is diverted to drain. If a proportion ofthe catholyte is used for pH control, then the catholyte can be dosed tothe anode stream either before or after it enters the anode chamber.

The output solution can then be directed to tank 70. The pH of suchoutput solution can be measured by a meter 72. If the pH does not fallwithin the desired parameters, a valve 76 can be opened and the contentsof tank 70 can be drained to waste. Meter 72 can be linked to a pump andvalve system 66 to adjust the level of catholyte dosed to the anodechambers thereby enabling the pH of the output solution to be adjustedto bring the output solution within the desired pH range. If the pH ofthe output solution is determined to fall within the desired parameters,valve 76 can be kept closed and the output solution can be allowed tofill tank 70. Other properties of the output solution, such as redoxpotential or AFC, could also form the basis of the measurement andcontrol system consisting of meter 72 and adjustable pump and valvesystem 66.

Storage tank 70 may include various level detectors for monitoringliquid levels in the tank. For example, a level detector 90 may beactivated by an extra high level of output solution within the tank,raising an alarm and stopping production. Low level detector 94 may beactivated when the level of the output solution falls to a low level,raising an alarm and preventing further dispensing to the appropriatereceptacle. As the output solution is dispensed and after a period oftime below the level of detector 94, production of output solution maybe re-commenced. From the storage tank, the output solution can bedistributed in individual nebulizers, inhalers, or ampules. Where theelectrolyzed solution is to be administered by humidifier or misting,the electrolytic cell system may be functionally coupled to a humidifieror fogger. Of course, the above-described processing steps of producingan electrolyzed saline solution are only exemplary and otherelectrochemical processes could be used to produce an electrolyzedsaline solution of embodiments of the present invention.

FIG. 3 shows an embodiment of an electrolytic cell 300 used in certainmethods of producing an electrolyzed saline solution according to anembodiment of the present invention. In this embodiment, cell 300comprises co-axial cylindrical and rod electrodes 302, 304 respectively,separated by a semi-permeable ceramic membrane 306 co-axially mountedbetween the electrodes thus splitting the space between the electrodesto form two chambers 308 and 310. Cylindrical electrode 302, which isthis embodiment forms the anode, is typically made from commerciallypure titanium coated with a ruthenium oxide and iridium oxide-basedelectrocatalytic (active) coating suitable for the evolution of chlorinefrom a chloride solution. Rod electrode 304, which in this embodimentforms the cathode, is typically made from titanium and can be machinedfrom an 8 mm stock bar to a uniform cross-section over its effectivelength, which is typically about 210 mm±0.5 mm. Of course, it will beunderstood by one of skill in the art that other suitable materials andconfigurations can be used to fabricate electrodes 302 and 304 to allowthese electrodes to perform their necessary function. Also, eitherelectrode can serve as the anode and similarly either electrode canserve as the cathode. If the rod is used as an anode, it is coated witha coating, such as ruthenium oxide and iridium oxide basedelectrocatalytic (active) coating, for example, suitable for theevolution of chlorine from a chloride solution. Semi-permeable ceramicmembrane 306 forming a separator and creating the anode and cathodechambers 308 and 310 can be composed of aluminum oxide (80%), zirconiumoxide (18.5%) and yttrium oxide (1.5%), and preferably has a porosity ofabout 50-70%, a pore size of 0.3 to 0.5 microns and a wall thickness of0.5 mm+0.3 mm/−0.1 mm. The ceramic of certain embodiments of membrane306 is described in the specification of patent application GB 2354478(Sterilox Medical (Europe) Limited), the subject matter of which isincorporated herein by reference. Ceramic membrane 306 can be made ofany other suitable semi-permeable or ion-selective material of ceramicsother than the aluminum oxide, zirconium oxide and yttrium oxide ceramicdescribed above.

Generally, the surface area of the anode can be largely defined by thequantities of output solution desired to be produced and available freechlorine content desired in that solution. However, in order to providea system that is of a size appropriate for commercial installation andto produce the quantities of biocidal solution of the invention oftenrequired, an anode surface area of 0.065 to 0.095 m², inclusive of allintermediate values, can be utilized. Such a surface area can be made upby a number of electrolytic cells working in parallel. An anode area of0.070 to 0.090 m² is more preferable, and an anode surface area of 0.075to 0.085 m² is even more preferable. In certain embodiments, eight cellsare arranged in parallel and the current density on the surface of eachanode is within the range 1.5 to 2.5 kAm⁻², more preferably 1.7 to 2.2kAm⁻², and still more preferably 1.85 to 1.95 kAm⁻².

In this embodiment, cell 300 is provided with entry passages 312 and 314to permit the saline solution to enter cell 300 and flow upwards throughthe anode and cathode chambers 308 and 310 to be discharged as anolyteand catholyte through exit passages 316 and 318 respectively. Theanolyte containing available free chlorine constitutes the outputsolution.

As previously described in reference to FIG. 2, in certain embodiments,in order to provide a preferred amount of output solution within areasonable period of time, a group of cells can be connected together toform a cell pack 63. For example, a cell pack comprising eight cellsconnected together in parallel hydraulically and in series electricallymay generate about 200 liters/hour of output solution.

When using higher volume generators, the flow rate through the anodechamber may vary between 100 to 220 l/h. For example, the flow rate maybe 150 to 210 l/h, or may be 185 to 205 l/h is even more preferred. Theflow rate can also be any value within the expressed ranges. Using lowervolume generators, the flow rate through the anode chamber may be in therange of 10-50 l/h, such as, for example, 30 l/h. The person skilled inthe art will appreciate that the flow rate can be altered beyond such arange but still produce the solution of embodiments of the invention byvarying the number of cells/surface area of anode. For example, the flowrate per anode surface area of 1.25×10³ to 2.75×10³ lh⁻¹ m⁻² can be usedproduce an embodiment of an electrolyzed saline solution of theinvention. The flow rate can also take any value with the aforementionedrange. Preferably, the flow rate is 1.87×10³ to 2.63×10³ lh⁻¹ m⁻² andmore preferably the flow rate is 2.31×10³ to 2.56×10³ lh⁻¹ m⁻². Theskilled person can obtain the required current to produce a suitablesolution by setting the flow rate to that just described and varying thecurrent until the solution produced has the suitable specifications.

In certain embodiments, the current range is 15 to 25 A, inclusive ofall intermediate values. In certain embodiments, a current range of 17to 22 A is used and in certain embodiments a current range of 18.5 to19.5 A is used.

The residual salt concentration of an embodiment of an electrolyzedsaline solution can be from 2.0 g/l to 90 g/l. This residual saltconcentration can result from the entire desired amount of salt beingadded during the input and pre-processing stage or less than the entiredesired amount of salt being added during the input and pre-processingstage and the remainder of the desired amount of salt being added afterthe production stage.

Examples Ocular Irritation

An eye irritation study was conducted on six healthy New Zealand whiterabbits, free from evidence of ocular irritation and cornealabnormalities. The test article (0.1 ml hypochlorous acid, 689.5 ppmAFC) was placed into the conjunctival sac of one eye of each rabbit. Thecontralateral eye served as a control. The eyes were examined and scoredby the Draize technique for any evidence of irritation or abnormalitiesof the cornea, on days 1, 2, and 3 post dose. The primary eye irritationscore of each rabbit, each day was calculated. All eyes appeared normalat each observation period and there were no abnormal physical signsnoted. In conclusion, under the test conditions of this study,hypochlorous acid (689.5 ppm AFC) showed no ocular irritation.

Dermal Irritation

A skin irritation study was conducted on six healthy New Zealand whiterabbits. The test article (0.5 ml hypochlorous acid, 689.5 ppm AFC) wasapplied to one intact and one abraded site on the clipped back of eachrabbit. Skin reactions were evaluated by the Draize technique at 24 and72 hours after dosing and the primary irritation index was calculated.There was no erythema or edema noted at any time period and there wereno abnormal physical signs noted during the observation period. Inconclusion, under the test conditions of this study, hypochlorous acid(689.5 ppm AFC) showed no dermal irritation.

Skin Sensitization

A skin irritation study was conducted on ten test and five controlalbino guinea pigs. The method used was the Magnusson and Kligmanguinea-pig maximization model. The animals were dosed (hypochlorousacid, 241-252 ppm AFC) by intradermal injection and by topicalapplication. Following initial exposure to the test substance, theanimals were subjected to approximately two weeks after topicalinduction to a “challenge” exposure of the test substance (50% v/v) inorder to establish whether a hypersensitivity state had been induced. Inthis study, there was no evidence of delayed contact hypersensitivity.In conclusion, under the test conditions, hypochlorous acid (241-252 ppmAFC) demonstrated no skin sensitization.

Acute Oral Toxicity

A skin irritation study was conducted on ten fasted rats (five femaleand five male). No control animals were included in this study. Allanimals received a single oral gavage dose of the test substance(hypochlorous acid, 241-252 ppm AFC), at the dose level of 2000 mg/kgbodyweight. All animals were killed and examined microscopically at theend of the observational period, (Day 15). All animals were consideredto have achieved satisfactory weight gain throughout the study.Macroscopic examination of animals on Day 15 revealed no abnormalities.In conclusion, under the test conditions of this study, hypochlorousacid (241-252 ppm AFC, 2000 mg/kg) demonstrated no oral toxicity.

Bacterial Mutagenicity

In vitro assessment of the mutagenic potential of hypochlorous acid(241-252 ppm AFC) was examined using histidine dependent auxotrophicemutants of Salmonella typhimuium (strains TA1535, TA1537, TA98 and TA100and a tryptophan dependent mutant of Escherichia coli (strain CM891)were exposed to the test substance. Mutation assays were performed inthe absence and presence of liver S9 fraction preparations from Aroclor1254-induced rats. No evidence of mutagenic activity was observed withhypochlorous acid at the test concentration of 241-252 ppm.

In Vitro Microbiology Profile

Hypochlorous acid has rapid virucidal, bactericidal, sporicidal andfungicidal activity. It rapidly kills gram positive and gram negativebacteria, including antibiotic resistant species of MRSA and VRE. MRSAskin infections are becoming more prevalent and there is a perceivedneed for alternative medications for patients who are infected by MRSA.In vitro antimicrobial studies have shown hypochlorous acid to producegreater than log 5 kill within a 5 minute contact time against a rangeof wound pathogens including S. aureus, P. aeruginosa, E. coli,Enterococcus spp., and Candida spp., even at concentrations of ≦180 ppmof hypochlorous acid (Table 1), including activity against bacterialendospores.

Results demonstrate that hypochlorous acid solution, when generated byelectrolysis, is effective in laboratory suspension and carrier testswithin a 5 minute contact time against pathogens, includingStaphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa,Enterococcus faecalis, Aspergillus and Candida albicans.

TABLE 1 Exemplary pathogens killed by Hypochlorous acid 150-180 ppm, pH6.3-6.75. Bacterial Bacteria Endospores Viruses Fungi PseudomonasBacillus cereus Adenovirus type V Aspergillus niger aeruginosa Bacillussubtilis var HIV-1 Candida albicans Staphylococcus ClostridiumPoliovirus type 1 Trichophyton aureus sporogenes Human Flu virusmentagrophytes Enterococcus Orthopoxvirus faecium (VRE) Human NorovirusSalmonella Murine Norovirus MS2 choleraesuis coliphage virusBactericidal, Mycobactericidal, Fungicidal, Sporicidal, and VirucidalSuspension Tests

Bactericidal activity suspension tests were performed using hypochlorousacid (at 180 ppm) against Staphylococcus aureus ATCC 6538 andPseudomonas aeruginosa ATCC 15442 and Enterococcus faecium ATCC 10541.Stock culture of Staphylococcus aureus ATCC 6538, Pseudomonas aeruginosaATCC 15442 and Enterococcus faecium ATCC 10541 were grown and maintainedon Tryptic Soy Agar at 37° C. Bacterial suspensions (1 ml) were added to1 ml of 0.3% BSA and 8 ml of hypochlorous acid at a range ofconcentrations at 20° C. After an exposure time of 5 minutes, 1 mlsamples were neutralized using universal quench. All samples wereserially diluted, plated out on Tryptic Soy Agar, incubated at 37° C.for 3 days and colonies forming units counted.

Fungicidal activity tests were performed using hypochlorous acid(140-180 ppm) against Candida albicans ATCC 10231 and Aspergillus nigerATCC 16404. Stock culture of Candida albicans ATCC 10231 and Aspergillusniger ATCC 16404 were grown and maintained on Malt Extract Agar at 30°C. Fungal suspensions (1 ml) were added to 1 ml of sterile distilledwater and 8 ml of hypochlorous acid solution at a range ofconcentrations at 20° C. After an exposure time of 5 minutes, 1 mlsamples were neutralized using standard quench solution. All sampleswere serially diluted, plated out on Tryptic Soy Agar, incubated at 37°C. for 3 days and colonies forming units counted.

Sporicidal activity tests were performed using hypochlorous acidsolution against Bacillus cereus CIP 7803, Bacillus subtilis CIP 7718,Clostridium sporogenes CIP 7939. Stock spore suspensions of Bacilluscereus CIP 7803, Bacillus subtilis CIP 7718, Clostridium sporogenes CIP7939 were obtained from the Pasteur Institute's National Collection forthe Culture of micro-organisms. Spore suspensions (1 ml) were added to 4ml of sterile distilled water and 5 ml of hypochlorous acid solution ata range of concentrations at 20° C. After an exposure time of 60minutes, 1 ml samples were neutralized using standard quench solution.All samples were serially diluted, plated out on selective agar,incubated aerobically or anaerobically at either 30° C. or 37° C. for 72hours and colonies forming units counted.

Virucidal activity tests were performed using hypochlorous acid againstPolio Enterovirus 1 Sabin strain, Adenovirus type V and Orthopoxvirus.Polio Enterovirus 1, SABIN sock cultures were maintained on Vero cells,Adenovirus, type V, cultured on KB cells and Orthopoxvirus from thevaccine cultured on Vero cells. Viral suspensions (0.5 ml) were added to0.5 ml of hypochlorous acid solution at a range of concentrations at 20°C. Viral suspensions were exposed to hypochlorous acid for 15, 30 and 60minutes. Following incubation, all samples were serially diluted andviruses cultured according to standard procedures.

The effectiveness of hypochlorous acid against Norovirus (NV) and MS2coliphage virus was evaluated using non-culturable human NV measured byRT-PCR and against two other surrogate viruses, coliphage MS2 and murinenorovirus, detected by infectivity and RT-PCR. Norovirus, geneticallycharacterized as genotype II.4. was obtained from patient's stools of anoutbreak of gastroenteritis at the University of North Carolina campusin 2004. Stools were made into 1% stool suspensions in phosphatebuffered saline (PBS, pH 7.5) on the day of an experiment. BacteriophageMS2 was used as a surrogate for norovirus and cultivated using E. coliFamp (ATCC 700891). Murine norovirus a surrogate for human norovirus wasobtained from the Skip Virgin lab in St. Louis and was cultivated bycell culture in Raw cells (ATCC TIB-71, Virginia, US). Virus suspensions(25 μl) consisting of 1% norovirus stool suspension and MS2 stock weretreated with 1.2 ml of hypochlorous acid solution (20-200 ppm). Afterspecified contact times, 25 μl of 6% sodium thiosulfate was added into1.2 ml chlorine+virus solution to neutralize any residual hypochlorousacid activity.

Broth cultures of either M. terrae (ATCC 15755) and M. avium (ATCC15769) were grown for up to 35 days at 35° C. Mycobacteria suspensions(1 ml) were added to 1 ml of 0.3% BSA and 8 ml of hypochlorous acidsolution at a range of concentrations at 20° C. After an exposure timeof 5 minutes, 1 ml samples were neutralized using standard quenchsolution. The plates were incubated for 4-5 weeks at 35° C. and coloniescounted.

Results shows that hypochlorous acid (150-180 ppm) effectively kills allorganisms tested in the suspension assays. Passes were achieved after 5minutes contact time against Pseudomonas aeruginosa, Staphylococcusaureus, Enterococcus faecium, Candida albicans, Aspergillus niger,Mycobacterium terrae and avium. Passes were achieved after 60 minutescontact time against Clostridium sporogenes, Bacillus subtilis var.niger, Bacillus cereus endospores and 15 minutes contact time againstPoliovirus Enterovirus 1, Adenovirus, type V, Orthopoxvirus from vaccine(Table 2). Additionally, suspension tests showed that exposure of humannorovirus, murine norovirus and coliphage MS2 to hypochlorous acidsolution at the dose range of 20-200 mg/L achieved 3 log₁₀ reductions ofboth MS2 and human norovirus within a contact time of 20 seconds.

TABLE 2 Reduction in the number of surviving cells after a contact timeof 5 mins at 20° C. ± 1° C. Test Pass Requirement Test Result TestOrganism Log reduction Log Reduction Pseudomonas aeruginosa ATCC 1544210⁵ in 60 min >10⁵ in 5 min Staphylococcus aureus ATCC 6538 10⁵ in 60min >10⁵ in 5 min Enterococcus faecium ATCC 10541 10⁵ in 60 min >10⁵ in5 min Candida albicans 10⁴ in 60 min >10⁴ in 5 min ATCC 10231Aspergillus niger 10⁴ in 60 min >10⁴ in 5 min ATCC 16404 Bacillus cereus10⁶ in 60 min >10⁶ in 60 min CIP 7 803 Bacillus subtilis var. niger CIP7 718 10⁶ in 60 min >10⁶ in 60 min Clostridium sporogenes 10⁶ in 60 min>10⁶ in 60 min CIP 7 939 Mycobacterium terrae 10⁶ in 60 min >10⁵ in 5min ATCC 15755 Mycobacterium avium 10⁶ in 60 min >10⁵ in 5 min ATCC15769 Orthopoxvirus from vaccine 10⁴ in 60 min >10⁴ in 15 minAdenovirus, type V 10⁴ in 60 min >10⁴ in 15 min Poliovirus Enterovirus 110⁴ in 60 min   10⁴ in 15 minBactericidal, Fungicidal and Virucidal Carrier Tests

Carriers (glass slides) were inoculated with either Salmonellacholerasuis, Pseudomonas aeruginosa and Human influenza A, Enterococcusfaecium, HIV, Trichophyton mentagrophytes or Staphylococcus aureus.These were then dried following the protocol guidelines and exposed tohypochlorous acid at <180 ppm for various contact times and cultured forviability.

For Norovirus and MS2 Coliphage Virus carrier tests, No. 4 polishedstainless steel and ceramic tile were used as representative non-porousand porous surfaces, respectively. Virus suspensions (20 μl) consistingof 1% norovirus stool suspension (human Norovirus type II) and MS2 phagestock were spotted onto the center of each carrier surface in triplicate(i.e. three different squares per experiment). As a negative control, 20μl of sterile PBS (pH 7.5) was spotted onto the carrier surface. Thematerial was allowed to dry on each surface for 2-3 hours in a laminarflow hood. Individual surfaces were transferred with sterile forceps to24 well plates. After specified contact times, 0.275 μl of 16% beefextract and 25 μl of 6% sodium thiosulfate were added into 1.2 mlchlorine solution to elute viruses and neutralize any residualhypochlorous acid activity. Plates were mixed for 20-minutes on a rotarydevice to facilitate virus elution from the test surfaces.

Tests passes (Table 3) were achieved after 2 minutes contact timeagainst Salmonella cholerasuis, Pseudomonas aeruginosa and Humaninfluenza A and after 5 minutes contact time Enterococcus faecium, HIV,Trichophyton mentagrophytes and Staphylococcus aureus. Additionally,carrier test results showed that hypochlorous acid on ceramic tiles andstainless steels inactivated MS2 and human norovirus by >3 log¹⁰ basedon infectivity alone and infectivity and RNA testing, after 1 min ofcontact time with hypochlorous acid (20-200 ppm).

TABLE 3 Carrier Test Data Microorganism Time to achieve pass HIV-1 5 minEnterococcus faecium (VRE) 5 min Pseudomonas aeruginosa 2 minStaphylococcus aureus 5 min Salmonella choleraesuis 2 min Trichophytonmentagrophytes 5 min Human Influenza A 2 min

Modifications of the disclosed embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art andsuch modifications are within the scope of the present invention. Allreferences cited herein are incorporated by reference in their entirety.

What is claimed is claim:
 1. A method for treating a conditioncharacterized by chronic type I or type IV hypersensitivity, comprising:administering to a patient in need thereof one to four times daily aneffective amount of a hypochlorous acid composition to an affectedregion sufficient to maintain the hygiene of the affected region,wherein the composition is produced by electrolysis of saline, andwherein the composition has an available free chlorine content of from20 to 1000 ppm that is at least 90% hypochlorous acid relative to thetotal concentration of hypochlorous acid, hypochlorite, and Cl₂.
 2. Themethod of claim 1, wherein the condition is a condition of the eye, ear,nose, mouth, or throat.
 3. The method of claim 2, wherein the ocularcondition includes conjunctivitis, blepharitis, external hordeolum,internal hordeolum, uveitis, canaliculitis, and/or dacrocystitis.
 4. Themethod of claim 1, wherein the hypochlorous acid has a pH of from 4 to7.
 5. The method of claim 1, wherein the hypochlorous acid has anavailable free chlorine content of above 200 ppm.
 6. The method of claim4, wherein the available free chlorine consists essentially ofhypochlorous acid as an active agent.
 7. The method of claim 1, whereinthe condition involves one or more of rhinitis, rhinorrhea, nasalcongestion, otitis media, external otitis, pharyngitis, and stomatitis.8. The method of claim 1, wherein the condition is delayed-typehypersensitivity.
 9. The method of claim 1, wherein the condition isimmediate-type hypersensitivity.
 10. The method of claim 1, wherein thecomposition is the form of a cream, gel, foam, aerosol, or solution. 11.The method of claim 1, wherein the composition is administered to theskin.